The goal of the proposed investigation is to achieve a better understanding of the molecular pathology of otosclerosis and ultimately develop better forms of treatment and prevention. The specific aims are to investigate bone metabolism of the otic capsule of normal mice and mice with genetic defects which give rise to otosclerosis in humans. We will apply what we learn from the mouse model to achieve a better understanding of factors which may result in abnormal otic capsule remodeling in humans. To accomplish this we will obtain bone specimens from normal patients and patients with otosclerosis, and study osteoblast bone cells in culture. We will apply what we learn from the mouse studies to normal human otic capsule physiology and determine which molecular factors are important in the initiation of otic capsule remodeling. Specifically, we will study defects in type 1 collagen gene expression and determine what effects these defects have on osteoblast physiology that may lead to the development of otosclerosis. If successful, the proposed study will result in a better understanding of the molecular factors involved in the development of otosclerosis, the development of genetic tests that will allow for identification of individuals who are at risk for developing otosclerosis, and an in vitro method for evaluating potential therapeutic agents.